The present invention relates to methods to prepare N-Boc protected biphenylalaninol, which is a key intermediate in the synthesis of pharmaceutically active compounds, e.g. neutral endopeptidase (NEP) inhibitors (see e.g. U.S. Pat. No. 4,722,810 and EP0059442.
R-biphenylalaninol is a novel compound. However, S-biphenylalaninol is mentioned and used in PCT-application WO9902153 (Table 1, page 25). However, the origin/preparation of this material is not disclosed. The synthesis of the racemic compound is described in CN101362708 (based on information disclosed in English abstract) The route described therein, however, is relatively long and requires an additional resolution step to obtain the desired enantiomerically enriched product. The S-enantiomer of Boc protected biphenyl alaninol has also been reported in U.S. Pat. No. 7,618,981; US2007056469; WO2005107762; WO2007056469; and WO2008138561. The typical synthetic method described therein to prepare the S-enantiomer of Boc protected biphenyl alaninol is based on the hydride reduction of Boc-protected biphenyl alanine which in turn can be prepared from enantiomerically pure biphenyl alanine using well established chemistry (Greene's Protective Groups in Organic Synthesis, 4th edition, page 725).
Several synthetic methods for preparation of D-biphenyl alanine have been reported. However, these are based on the use of expensive raw materials (D-Tyr; J. Med. Chem. 1995, 38, 1689) or rely on an (enzymatic) resolution of the corresponding racemic ester (EP1980622), which makes them less attractive from a commercial point of view. In addition, synthetic routes based on asymmetric hydrogenation of the N-acyl dehydroamino acid derivatives are known (Adv. Synth. Cat. 2003, 345, 308). The disadvantage of this approach is that the required hydrolysis of the N-acetyl group is time consuming and may give rise to erosion of enantiomeric excess.
Therefore, there is a strong need to develop inexpensive methods to prepare N-Boc protected biphenylalaninol. It is found that the present invention meets this objective and thus provides a process that is industrially advantageous.